2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)-malononitrile ([F-18]FDDNP) PET imaging has been used for classifying and staging progressive diseases, like Alzheimer's disease (AD) and Chronic Traumatic Encephalopathy (CTE). Almost two decades of clinical research experience in the U.S., Europe, and Asia has demonstrated the ability of [F-18]FDDNP to differentiate Alzheimer's disease (AD) from normal aging, mild cognitive impairment, and several other neurodegenerative diseases (e.g., progressive supranuclear palsy, dementia with Lewy bodies, Down syndrome). The ability of [F-18]FDDNP to differentiate AD from normal aging is comparable to that of 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG). Moreover recent clinical research demonstrates a distinct [F-18]FDDNP binding pattern in retired athletes and military personnel with a history of traumatic brain injury and suspected CTE, and this pattern can be readily differentiated from that of AD. Currently there is no available biomarker that can detect suspected CTE in living people at risk, and other PET ligands for this purpose are very early in their development.
Liu et al. discloses one method for the automated radiosynthesis of [F-18]FDDNP. See Liu, J. et al., High-yield, automated radiosynthesis of 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene-malononitrile([18F]FDDNP) ready for animal or human administration, Mol. Imaging Biol., 9: 6-16 (2007). However, this previously reported synthesis of [F-18]FDDNP for the preparation of multi-dose quantities of tracer has certain limitations. First, this method uses a rather complex pre-purification of the F-18 fluorination reaction mixture using cumbersome multiple cartridges and evaporation processes prior to semi-preparative HPLC purification. Second, it uses toxic and potentially harmful organic solvents in the pre-purification and semi-preparative HPLC purification steps (e.g., dichloromethane, methanol (MeOH), and tetrahydrofuran). Third, autoradiolytic decomposition of [F-18]FDDNP could potentially occur during the pre-purification and HPLC purification processes. Autoradiolytic decomposition can generally be a serious issue with F-18 labeled compounds with high specific activities leading to a reduction in radiochemical yields, decreased product stability, and increase in radiochemical impurities. In the previously reported synthesis, the formulation and sterilization of the product in human serum albumin (HSA) also lowers the radiochemical yield of the final product to about 27%. Radiochemical yields are particularly important because positron emitter labeled biomarkers like [F-18]FDDNP have a relatively short half-life (half-life of F-18 isotope is 110 minutes).
Two considerations are important for the use of these biomarkers in clinical settings, which is the primary intent for the use of [F-18]FDDNP to characterize CTE and AD, among other neurodegenerative diseases. First, such biomarkers or probes are often produced in one geographic location (e.g., where a cyclotron is located), but used in remote geographic regions. Transportation of F-18 labeled biomarkers over relatively longer geographical distances will invariably result in lower final usable doses. It is thus critically important to achieve as high a radiochemical yield as possible so that one batch of [F-18]FDDNP can be divided into multiple doses that can efficiently be used even in geographically remote locations. Second, in U.S. Food and Drug Administration (FDA)-sponsored clinical trials and clinical use of PET biomarkers, the easiness, reproducibility and reliability of the final product ready for injection are essential.